N&#39;-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors

ABSTRACT

This invention relates to N&#39;-alkyl-spiro-isoquinoline-pyrrolidine tetrones and their pharmaceutically acceptable salts thereof, to processes for their preparation, to methods for using the compounds, and to pharmaceutical perparations thereof. The compounds have pharmaceutical properties which render them beneficial for the prevention or treatment of diabetes melitus associated complications.

BACKGROUND OF THE INVENTION

This invention relates to N'-alkyl-spiro-isoquinoline-pyrrolidinetetrones and their pharmaceutically acceptable salts thereof, toprocesses for their preparation, to methods for using the compounds, andto pharmaceutical preparations thereof. The compounds havepharmaceutical properties which render them beneficial for theprevention or treatment of complications associated with diabetesmellitus.

The use of insulin and/or oral hypoglycemic agents in the treatment ofdiabetes mellitus has prolonged the life of many of these patients.However, their use has not had a demonstrable impact on the developmentof diabetic complications such as neuropathy, nephropathy, retinopathy,cataracts and vascular disease which accompany the underlying metabolicdisorder. There is little question that chronic hyperglycemia plays amajor role in the genesis of these complications, and that completenormalization of blood glucose would likely prevent most if not allcomplications. For a number of reasons, though, chronic normalization ofblood glucose has not been achieved with the currently availabletherapies.

The long-term complications of diabetes develop in tissues where glucoseuptake is independent of insulin. In these tissues, which include thelens, retina, kidney and peripheral nerves, the systemic hyperglycemiaof diabetes is rapidly transposed into high tissular concentrations ofglucose. In all of these tissues this excess glucose is rapidlymetabolized by the sorbitol pathway. The intense diabetes-induced fluxof glucose through this pathway appears to initiate a cascade ofbiochemical alterations which slowly progress to cell dysfunction andstructural damage. Aldose reductase, the key enzyme in the sorbitolpathway, reduces glucose to sorbitol at the expense of the cofactorNADPH. In animal models of diabetes, compounds which inhibit aldosereductase have been shown to prevent the biochemical, functional andmorphological changes induced by hyperglycemia. Early studies by J. H.Kinoshita and collaborators implicated aldose reductase in the etiologyof diabetic cataracts. More recent studies have provided compellingevidence that aldose reductase also plays a significant role in theinitiation of diabetic nephropathy, retinopathy and neuropathy (cfMcCaleb et al, J. Diab. Comp., 2, 16, 1989; Robison et al, Invest.Ophthalmol. Vis. Sci., 30, 2285, 1989; Notvest and Inserra, Diabetes,36, 500, 1987.

PRIOR ART

The closest prior art is allowed U.S. Ser. No. 357,563, filed May 26,1989, which discloses the spiro-isoquinoline-pyrrolidine tetrones offormula ##STR1## useful as aldose reductase inhibitors for treatingcomplications of diabetes and galactosemia.

SUMMARY OF INVENTION

The N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones of the presentinvention are represented by formula (I): ##STR2## wherein R¹ and R² areindependently hydrogen, alkyl containing 1 to 6 carbon atoms, halogen,lower alkoxy containing 1 to 6 carbon atoms, trifluoromethyl, nitro,aryl or aryl(lower alkyl)oxy wherein aryl contains 6 to 10 carbon atomsand lower alkyl contains 1 to 6 carbon atoms; R³ is hydrogen, loweralkyl containing 1 to 6 carbon atoms, aryl, aryl(lower alkyl) or halogensubstituted aryl(lower alkyl) wherein aryl contains 6 to 10 carbon atomsand lower alkyl contains 1 to 6 carbon atoms, or benzothiazole ofstructural formula ##STR3## wherein R⁵ is hydrogen, alkyl containing 1to 6 carbon atoms, lower alkoxy containing 1 to 6 carbon atoms,trifluoromethyl, nitro, aryl or aryl(lower alkyl)oxy wherein arylcontains 6 to 10 carbon atoms and lower alkyl contains 1 to 5 carbonatoms; and R⁴ is alkyl containing 1 to 12 carbon atoms, aryl, aryl(loweralkyl) wherein aryl contains 6 to 10 carbon atoms and lower alkylcontains 1 to 6 carbon atoms, acyl, carboalkoxy, or --(CH₂)_(n) CO₂ H,--(CH₂)_(n) OH, wherein n is 1 to 6.

A more preferred group of compounds of the present invention are thecompounds of formula (I) wherein R¹ and R² are independently hydrogen orhalogen; R³ is a mono- or dihalogen substituted aryl(lower alkyl)wherein aryl contains 6 carbon atoms and lower alkyl contains 1 to 3carbon atoms, or benzothiazole of structural formula ##STR4## wherein R⁵is hydrogen, halogen or trifluoromethyl; and R⁴ is alkyl containing 1 to3 carbon atoms.

The most preferred compounds of the present invention are set forthbelow:

2-[(4-bromo-2-fluorophenyl)methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone;

2-[(4-bromo-2-fluorophenyl)methyl]-1'-ethylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone;

2-[(4-bromo-2-fluorophenyl)methyl]-1'-ethyl-6-fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone;

2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone;

1'-ethyl-6-fluoro-2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.

The compounds of formula (I) all possess at least one asymmetric carbonatom, namely the spiro carbon atom at position 3' of the pyrrolidinering. The compounds of formula (I) therefore exist, and may be isolated,in two or more stereoisomeric forms. This invention encompasses thecompounds of formula (I) in racemic form or in any optically activeform.

The N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones can be prepared bythe processes described hereinafter.

A method is provided for preventing or relieving diabetes mellitusassociated complications in a diabetic mammal by administering to saidmammal a prophylactic or alleviating amount of the compounds of formula(I). Such complications include neuropathy, nephropathy, retinopathy,keratopathy, diabetic uveitis, and cataracts.

The compounds of formula (I), when admixed with a pharmaceuticallyacceptable carrier, form a pharmaceutical composition which can be usedaccording to the preceding method.

The N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones of this inventionmay be administered to mammals, for example, man, cattle, or rabbits,either alone or in dosage forms, i.e., capsules or tablets, combinedwith pharmacologically acceptable excipients.

The compounds of this invention may be given orally. However, the methodof administering the present active ingredients of this invention is notto be construed as limited to a particular mode of administration. Forexample, the compounds may be administered topically directly to the eyein the form of drops of sterile, buffered ophthalmic solutions,preferably of pH 7.2-7.6. Also, they may be administered orally in solidform containing such excipients as starch, milk sugar, certain types ofclay and so forth. They may also be administered orally in the form ofsolutions or they may be injected parenterally. For parenteraladministration, they may be used in the form of a sterile solution,preferably of pH 7.2-7.6, containing a pharmaceutically acceptablebuffer.

The dosage of the N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones willvary with the form of administration and the particular compound chosen.Furthermore, it will vary with the particular host under treatment.Generally, treatment is initiated with small dosages substantially lessthan the optimal dose of the compound. Thereafter, the dosage isincreased by small increments until efficacy is obtained. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects. For topicaladministration, a 0.05-1.0% solution may be administered dropwise in theeye. The frequency of instillation varies with the subject undertreatment from a drop every two or three days to once daily. For oral orparenteral administration a preferred level of dosage ranges from about0.1 mg to about 1.0 mg per kilo of body weight per day, althoughaforementioned variations will occur. However, a dosage level that is inthe range of from about 0.1 mg to about 1.0 mg per kilo of body weightper day is most satisfactory.

Unit dosage forms such as capsules, tablets, pills and the like maycontain from about 5.0 mg to about 25.0 mg of the active ingredients ofthis invention with a pharmaceutical carrier. Thus, for oraladministration, capsules can contain from between about 5.0 mg to about25.0 mg of the active ingredients of this invention with or without apharmaceutical diluent. Tablets, either effervescent or noneffervescent,can contain between about 5.0 to 25.0 mg of the active ingredients ofthis invention together with conventional pharmaceutical carriers. Thustablets, which may be coated and either effervescent or noneffervescent,may be prepared according to the known art. Inert diluents or carriers,for example, magnesium carbonate or lactose, can be used together withconventional disintegrating agents for example, magnesium stearate.

The N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones also can be used incombination with insulin or oral hypoglycemic agents to produce abeneficial effect in the treatment of diabetes mellitus. In thisinstance, commercially available insulin preparations or oralhypoglycemic agents, exemplified by acetohexamide, chlorpropamide,tolazamide, tolbutamide and phenformin, are suitable. The compoundshereof can be administered sequentially or simultaneously with insulinor the oral hypoglycemic agent. Suitable methods of administration,compositions and doses of the insulin preparation or oral hypoglycemicagent are described in medical textbooks; for instance, Physicians' DeskReference, 42 ed., Medical Economics Co., Oradell, N.J., U.S.A., 1988.

The aldose reductase inhibiting property of the compounds of thisinvention and the utilization of the compounds in preventing,diminishing and alleviating diabetic complications are demonstrable inexperiments using galactosemic rats, see Dvornik et al., Science, 182,1146 (1973). Such experiments are exemplified hereinbelow after thelisting of the following general comments pertaining to theseexperiments:

(a) Four or more groups of six male rats, 50-70 g, Sprague-Dawleystrain, were used. The first group, the control group, was fed a mixtureof laboratory chow (rodent Laboratory Chow, Purina) and glucose at 20%(w/w %) concentration. An untreated galactosemic group was fed a similardiet in which galactose was substituted for glucose. The third group wasfed a diet prepared by mixing a given amount of the test compound withthe galactose containing diet. The concentration of galactose in thediet of the treated groups was the same as that for the untreatedgalactosemic group.

(b) After four days, the animals were killed by euthanization. Both thelens and sciatic nerve were removed, weighed and stored frozen forpolyol determination.

(c) The polyol determination was performed by a modification of theprocedure of M. Kraml and L. Cosyns, Clin. Biochem., 2, 373 (1969). Onlytwo minor reagent changes were made: (a) the rinsing mixture was anaqueous 5% (w/v) trichloroacetic acid solution and (b) the stocksolution was prepared by dissolving 25 mg of dulcitol in 100 ml of anaqueous trichloroacetic acid solution. [N.B.: For each experiment theaverage value found in the tissue from rats fed the glucose diet wassubstracted from the individual values found in the corresponding tissuein galactose-fed rats to obtain the amount of polyol accumulated.] Thealdose reductase inhibiting effects of the compounds of formula (I) werealso tested by employing an in vitro testing procedure similar to thatdescribed by S. Hayman and J. H. Kinoshita, J. Biol. Chem., 240, 877(1965). In the present case the procedure of Hayman and Kinoshita wasmodified in that the final chromatography step was omitted in thepreparation of the enzyme from bovine lens.

The following tabulated results show that theN'-alkyl-spiro-isoquinoline-pyrrolidine tetrones of this invention showthe property that they are active both in vitro and in vivo and diminishthe accumulation of dulcitol in the lenses, sciatic nerves and diaphragmof rats fed galactose. The figures under L, N, and D represent thepercentage decrease of dulcitol accumulation in the tissues of the lens,sciatic nerve, and diaphragm, respectively, for treated rats as comparedto untreated rats.

    ______________________________________                                        ALDOSE REDUCTASE INHIBITORS                                                   ______________________________________                                         ##STR5##                                                                                      % lowering                                                           % inhibition                                                                           dulcitol accumulation                                                in vitro dose    in vivo                                              R.sup.1                                                                           R.sup.4   10.sup.-5 M                                                                              mg/kg % L   % N   % D                                ______________________________________                                        H   CH.sub.3  0          0.5   NS    50    61                                                          1.1   NS    76    75                                                          10.2  31    95    94                                 H   CH.sub.2 CH.sub.3                                                                       0          0.5   NS    37    56                                                          0.9   NS    65    73                                 F   CH.sub.2 CH.sub.3                                                                       0          0.5   NS    19    65                                                          1.0   NS    74    84                                 ______________________________________                                         ##STR6##                                                                                    % Lowering Galactitol                                                         Accumulation                                                   % Inhibition     Dose                                                         Vitro            mg/     In Vivo                                              R.sup.1                                                                           R.sup.4                                                                              R.sup.5                                                                              10.sup.-6 M                                                                            kg/day                                                                              (%) L (%) N (%) D                            ______________________________________                                        H   CH.sub.3                                                                             CF.sub.3                                                                             0        9.5   NS    82    100                              F   C.sub.2 H.sub.5                                                                      CF.sub.3                                                                             0        10    NS    NS     59                              ______________________________________                                    

PROCESS A

The N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones of the presentinvention were prepared by the following reaction scheme: ##STR7##wherein R¹, R², R³, R⁴, and R⁵ are as defined above.

PROCESS B

Some compounds of formula (I), wherein R¹, R², and R³ are as definedabove and R⁴ is acyl or carboalkoxy, can be made by the process B.##STR8## wherein R¹, R², and R³ are as defined above and R⁴ is acyl orcarboalkoxy.

Step a) Reacting either 2-bromobenzoic acid or 2-chlorobenzoic acid offormula (II) wherein R¹ and R² are as defined above with dimethylmalonate and NaH in the presence of a catalytic amount of CuBr toproduce the propanedioic acid dimethyl ester of formula (III) wherein R¹and R² are as defined above.

The 2-bromobenzoic acids or 2-chlorobenzoic acids of formula (II)required for the present invention are commercially available compoundsor can be prepared by known methods.

Step b) The propanedioic acid dimethyl ester of formula (III) can bereacted with thionyl chloride under refluxing conditions to produce thecorresponding acid chloride which upon treatment with an amine R³ --NH₂in the presence of triethylamine in a conventional solvent which doesnot adversely influence the reaction, for example, tetrahydrofuran, canproduce the compound of formula (IV) wherein R¹, R² and R³ are asdefined above.

Step c) The compound of formula (IV), wherein R¹, R² and R³ are asdefined above, is reacted with an inorganic base such as potassiumcarbonate in a conventional solvent which does not adversely influencethe reaction, for example, N,N-dimethylformamide, and subsequentaddition of the tert-butyl bromoacetate produces the compound of theformula (V), wherein R¹, R² and R³ are as defined above.

Step d) The compound of formula (V), wherein R¹, R² and R³ are asdefined above, is hydrolyzed with an organic acid such astrifluoroacetic acid in a conventional solvent which does not adverselyinfluence the reaction, for example, methylene chloride, to produce thecompound of formula (VI), wherein R¹, R² and R³ are as defined above.

Step e) The compound of formula (VI), wherein R¹, R² and R³ are asdefined above, can be reacted with thionyl chloride under refluxingconditions to produce the corresponding acid chloride, which upontreatment with R⁴ --NH₂ wherein R⁴ is as defined above produces theamide of formula (VII), wherein R¹, R², R³ and R⁴ are as defined above.However, in the case when R⁴ =Me the initially formed amide (VII, whenR⁴ =Me) cyclizes under these conditions to the final product (I, when R⁴=Me).

Step f) The amide of formula (VII), wherein R¹, R², R³ and R⁴ are asdefined above, is reacted with a base such as sodium hydride in aconventional solvent which does not adversely influence the reaction,for example, N,N-dimethylformamide, to produce the compound of theformula (I), wherein R¹, R², R³ and R⁴ are as defined above.

Step g) The propanedioic acid dimethyl ester of formula (III) can bereacted with thionyl chloride under refluxing conditions to produce thecorresponding acid chloride which upon treatment with Et₃ N in aconventional solvent which does not adversely influence the reaction,for example, tetrahydrofuran, can produce the compound of formula(VIII), wherein R¹ and R² are as defined above.

Step h) The compound of formula (VIII), wherein R¹ and R² are as definedabove, is reacted with aminoacetonitrile hydrochloride in the presenceof Et₃ N in a conventional solvent which does not adversely influencethe reaction, for example, N,N-dimethylformamide, produces the compoundof the formula (IX), wherein R¹ and R² are as defined above.

Step i) The compound of formula (IX), wherein R¹ and R² are as definedabove, is reacted with an inorganic base such as potassium carbonate ina conventional solvent which does not adversely influence the reaction,for example, N,N-dimethylformamide and subsequent addition of thetert-butyl bromoacetate produces the compound of formula (X), wherein R¹and R² are as defined above.

Step j) The compound of formula (X), wherein R¹ and R² are as definedabove, can be reacted with 2-aminothiophenols (R⁵ is as defined above)under refluxing conditions in a conventional solvent which does notadversely influence the reaction, for example, ethyl alcohol, andsubsequent treatment of the crude product with an organic acid such astrifluoroacetic acid in a conventional solvent which does not adverselyinfluence the reaction, for example, methylene chloride, to produce thecompound of formula (XI), wherein R¹, R² and R⁵ are as defined above.

Step k) The compound of formula (XI), wherein R¹, R² and R⁵ are asdefined above, can be reacted with thionyl chloride under refluxingconditions to produce the corresponding acid chloride which upontreatment with R⁴ --NH₂ (wherein R⁴ is as defined above) in aconventional solvent which does not adversely influence the reaction,for example, tetrahydrofuran, produces the compound of formula (XII),wherein R¹, R², R⁴, and R⁵ are as defined above. However, in the casethat the initially formed amide does not cyclize under the reactionconditions, cyclization can be achieved in a similar manner as that ofStep f.

The following examples further illustrate this invention:

EXAMPLE 12-[(4-Bromo-2-fluorophenyl)methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone Step A)(2-Carboxyphenyl)propanedioic Acid Dimethyl Ester

To a rapidly stirred cold suspension (0° C.) of 2-bromobenzoic acid(30.0 g, 149.32 mmol), cuprous bromide (2.14 g, 14.93 mmol) and dimethylmalonate (300 mL) was added NaH (80% in mineral oil, 10.75 g, 358.37mmol) over a 30 minute period, while a stream of dry N₂ was passed overthe mixture. After the addition of the NaH had been completed, themixture was stirred for 10 minutes at room temperature and 30 minutes at70° C. (external oil bath temperature). At this point, the suspensionhad turned to a solid mass, which was dissolved in H₂ O (1000 mL). Theaqueous layer was extracted with diethyl ether (3×500 mL) and wasacidified with HCl (2N). The mixture was extracted with EtOAc and driedover MgSO₄. Evaporation gave an off-white solid which was recrystallizedfrom Et₂ O/hexane (-20° C.) to give a white solid (34.2 g, 90.9%).

¹ H NMR (DMSO-d₆, 400 MHz): δ3.67 [s, 6H, --CH(CO₂ CH₃)₂ ], 5.72 [s, 1H,--CH(CO₂ CH₃)₂ ], 7.3 (d, J=7.76 Hz, 1H, Ar-H), 7.45 (dt, J=7.66 Hz,1.12 Hz, 1H, Ar-H), 7.6 (dt, J=7.66 Hz, 1.45 Hz, 1H, Ar-H), 7.94 (dd,J=7.8 Hz, 1.33 Hz, 1H, Ar-H), 13.2 (s, 1H, --CO₂ H).

IR (KBr, cm⁻¹): 3300-2700 (br), 1750 (s), 1730 (s), 1680 (s), 1430 (m),730 (m).

MS (m/e): 252 (M⁺), 220 (M⁺ --CH₃ OH), 188 (M⁺ --2×CH₃ OH).

Anal. Calcd.: C, 57.14; H, 4.80; Found: C, 57.05; H, 4.78.

M.P. 119°-120° C.

The following compound was prepared in substantially the same manner asthat of Example 1, Step a):

(2-Carboxy-6-fluorophenyl)propanedioic Acid Dimethyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ3.68 [s, 6H, (--CO₂ Me)₂ ], 5.79 (s, 1H,Ar-H), 7.12 (dd, J=10.06 Hz, 2.61 Hz, 1H, Ar-H), 7.33 (dt, J=8.48 Hz,2.64 Hz, 1H, Ar-H), 8.03 (dd, 8.77 Hz, 6.17 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 3400-2700 (br), 1730 (s), 1680 (s), 750 (m).

MS (m/e): 270 (M⁺), 238 (M⁺ --CH₃ OH), 210 (M⁺ --CH₃ OH, --CO), 151 (M⁺--CH₃ OH, --CO, --CO₂ CH₃).

M.P. 121.5°-123.0° C.

Step B)2-[(4-Bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylicAcid Methyl Ester

A mixture of (2-carboxyphenyl)propanedioic acid dimethyl ester (5.0 g,19.84 mmol) and SOCl₂ (20 g) was refluxed for 1 and 1/2 hours. Thevolatiles were removed in vacuo and the acid chloride was dissolved inTHF (20 mL). In a second flask were placed 4-bromo-2-fluorobenzylamine(4.67 g, 22.91 mmol), triethylamine (15.96 mL, 114.55 mmol) and THF (150mL). The contents of the first flask were added to the second flask andthe mixture was stirred for 30 minutes. The formed suspension was pouredinto H₂ O (1000 mL), stirred for 10 minutes and acidified with HCl (2N).The mixture was extracted with EtOAc and the organic layer was driedover MgSO₄. Evaporation gave a yellowish solid which was recrystallizedfrom acetone/ether/hexane (at -20° C.) to yield a white solid (6.01 g,74.6%).

¹ H NMR (DMSO-d₆, 400 MHz): δ[3.67, 3.99 (s, 3H, --CO₂ CH₃,tautomeric)], [5.06 (q, J=15.4 Hz), 5.29 (s), 2H, N--CH₂ --,tautomeric], 5.03 (s, 1H, --CHCO₂ CH₃, tautomeric), 7.07-8.44 (m, 7H,Ar-H, tautomeric).

IR (KBr, cm⁻¹): 1675 (s), 1610 (s), 1490 (s), 7.95 (m).

MS (m/e): 405 (M⁺), 373 (M⁺ --MeOH).

Anal. Calcd.: C, 53.22; H, 3.23; N, 3.45; Found: C, 52.91; H, 3.20; N,3.27.

M.P. 149°-150° C.

The following compound was prepared in substantially the same manner asthat of Example 1, Step b):

2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylicAcid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ3.98 (s, 3H, --CO₂ CH₃), 5.27 (s, 2H,--NCH₂ --), 7.08 (t, J=7.95 Hz, 2H, Ar-H), 7.2 (m, 1H, Ar-H), 7.34 (m,2H, Ar-H, --OH), 7.54 (m, 1H, Ar-H), 8.1-8.26 (m, 2H, Ar-H).

IR (KBr, cm⁻¹): 1680 (s), 1660 (s), 1610 (s), 785 (m).

MS (m/e): 423 (M⁺), 391 (M⁺ --CH₃ OH).

Anal. Calcd.: C, 50.97; H, 2.85; N, 3.30; Found: C, 50.86; H, 2.86; N,3.33.

M.P. 157°-158° C.

Step C)2-[(4-Bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid 1,1-Dimethylethyl Ester

To a suspension of2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylicacid methyl ester (4.79 g, 11.58 mmol), K₂ CO₃ (3.19 g, 23.16 mmol) inDMF (100 mL) was added tert-butyl bromoacetate (2.81 mL, 17.37 mmol).After stirring at 75° C. for 1 hour, the mixture was poured into H₂ O,extracted with EtOAc and dried over MgSO₄. Evaporation and purificationby flash chromatography (hexane/EtOAc, 4/1) gave a clear oil (5.69 g,94.5%).

¹ H NMR (DMSO-d₆, 400 MHz): δ1.04 [s, 9H, --C(CH₃)₃ ], 3.53 (s, 3H,--CO₂ CH₃), 3.60 [dd, J=17.7 Hz, 2H, --CH₂ CO₂ C(CH₃)₃ ], 5.14 (s, 2H,NCH₂ --), 7.17 (t, J=8.25 Hz, 1H, Ar-H), 7.36 (dd, J=8.36 Hz, 1.75 Hz,1H, Ar-H), 7.6 (m, 3H, Ar-H), 7.77 (dt, J=7.2 Hz, 1.27 Hz, 1H, Ar-H),8.19 (dd, J=8.25 Hz, 1.54 Hz, 1H, Ar-H).

IR (CHCl₃, cm⁻¹): 1720 (s), 1675 (s), 1360 (s), 765 (m).

MS (m/e): 520 (M+H)⁺, 464 [M⁺ --C(CH₃)₃ ].

The following compound was prepared in substantially the same manner asthat of Example 1, Step c):

2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid 1,1-Dimethylethyl Ester

¹ H NMR (DMSO-d₆, 200 MHz): δ1.1 (s, 9H, --CMe₃), 3.55 (s, 3H, --CO₂CH₃), 3.62 (d, J=1.75 Hz, 1H, --CH₂ CO₂ CMe₃), 3.75 (d, J=17.5 Hz, 1H,--CH₂ CO₂ CMe₃), 5.15 (s, 2H, --NCH₂ --), 7.15 (t, J=8.2 Hz, 1H, Ar-H),7.35 (d, J=8.2 Hz, 1H, Ar-H), 7.45-7.7 (m, 3H, Ar-H), 8.38 (dd, J=8.16Hz, 5.70 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1750 (s), 1720 (s), 1675 (s).

M/S (m/e): 538 (M+H)⁺, 481 (M⁺ +H, -tert-butyl).

Anal. Calcd.: C, 53.55; H, 4.12; N, 2.60; Found: C, 53.49; H, 4.00; N.2.63.

Step D)2-[(4-Bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid

A mixture of2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticacid 1,1-dimethylethyl ester (5.19, 9.81 mmol), CH₂ Cl₂ (100 mL) and CF₃CO₂ H (20 mL) was stirred at room temperature for 5 hours. The volatileswere removed in vacuo and the residue was purified by flashchromatography on acid washed silica gel (5% H₃ PO₄ in MeOH), to give awhite solid (4.12 g, 90.5%).

¹ H NMR (DMSO-d₆, 400 MHz): δ3.54 (s, 3H, --CO₂ CH₃), 3.64 (dd, J=17.67Hz, 2H, --CH₂ CO₂ H), 5.12 (dd, J=15.34 Hz, 2H, --NCH₂ --), 7.14 (t,J=8.22 Hz, 1H, Ar-H), 7.3 (d, J=8.3 Hz, 1H, Ar-H), 7.5-7.6 (m, 3H,Ar-H), 7.76 (d, 7.4 Hz, 1H, Ar-H), 8.16 (d, J=7.8 Hz, 1H, Ar-H), 12.35(s, 1H, --CO₂ H).

IR (KBr, cm⁻¹): 3280 (m), 3500-2500 (br), 1750 (s), 1720 (s), 1675 (s),1350 (s), 875 (m).

MS (m/e): 463 (M⁺), 445 (M⁺ --H--OH).

Anal. Calcd. for C₂₀ H₁₅ BrFNO₆.0.2H₂ O: C, 51.28; H, 3.30; N, 2.99;Found: C, 51.26; H, 3.48; N, 2.95.

M.P. 139°-140° C.

The following compound was obtained in substantially the same manner asthat of Example 1, Step d):

2-[(4-Bromo-2-fluorophenyl)methyl]-6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid

¹ H NMR (DMSO-d₆, 400 MHz): δ3.56 (s, 3H, --CO₂ CH₃), 3.6 (d, J=17.9 Hz,1H, --CH₂ CO₂ H), 3.8 (d, J=17.9 Hz, 1H, --CH₂ CO₂ H), 5.1 (dd, J=15.5Hz, 2H, --NCH₂ --), 7.12 (d, J=8.23 Hz, 1H, Ar-H), 7.31 (dd, J=8.28 Hz,1.68 Hz, 1H, Ar-H), 7.45 (dt, J=8.56 Hz, 2.5 Hz, 1H, Ar-H), 7.54 (dd,J=9.77 Hz, 1.89 Hz, 1H, Ar-H), 7.64 (dd, J=9.61 Hz, 2.46 Hz, 1H, Ar-H),8.23 (dd, J=8.79 Hz, 5.81 Hz, 1H, Ar-H), 12.67 (brs, 1H, --CO₂ H)

IR (KBr, cm⁻¹): 3400-2700 (br), 1745 (s), 1710 (s), 1670 (s), 770 (m).

MS (m/e): 481 (M⁺), 405 (M⁺ --CO₂, --CH₃ OH).

Anal. Cald.: C, 49.81; H, 2.93; N, 2.90; Found: C, 49.94; H, 3.03; N,2.84.

M.P. 132°-133.5° C.

Steps E, F)2-[4-Bromo-2-fluorophenyl)methyl]-1'-ethylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

A mixture of2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticacid (2.0 g, 4.31 mmol) and SOCl₂ (10 g) was refluxed for 1 hour. Thevolatiles were removed in vacuo and the acid chloride was dissolved inTHF (10 mL). In a second flask was placed a freshly prepared saturatedNH₂ Et/THF solution (20 mL) and the contents of the first flask wereadded slowly. After 10 minutes the mixture was poured into H₂ O,acidified with HCl (2N), extracted with EtOAc and the organic extractswere dried over MgSO₄. Evaporation gave a crude product which wasdissolved in DMF (10 mL) and NaH (80% dispersion in oil, 129.3 mg, 4.31mmol) was added portionwise. After 20 minutes the mixture was quenchedwith HCl (2N), extraced with EtOAc and dried over MgSO₄. Purification byflash chromatography (hexane/EtOAc, 4/1) and crystallization fromether/hexane (at -20° C.) gave a white solid (1.4 g, 70.7%).

¹ H NMR (DMSO-d₆, 400 MHz): δ1.01 (t, J=7.2 Hz, 3H, --NCH₂ CH₃), 3.4 (d,J=18.2 Hz, 1H, --CH₂ CONEt--), 3.48 (q, J=7.2 Hz, 2H, --NCH₂ CH₃), 3.52(d, J=18.2 Hz, 1H, --CH₂ CONEt--), 5.07 (s, 2H, --NCH₂ --), 7.15 (t,J=8.23 Hz, 1H, Ar-H), 7.33 (dd, J=8.3 Hz, 1.76 Hz, 1H, Ar-H), 7.53 (dd,J=9.84 Hz, 1.9 Hz, 1H, Ar-H), 7.61-7.65 (m, 2H, Ar-H), 7.78 (dt, J=7.65Hz, 1.43 Hz, 1H, Ar-H), 8.17 (dd, J=8.19 Hz, 1.49 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1720 (s), 1690 (s).

MS (m/e): 458 (M⁺), 387 (M⁺ --CONEt--), 359 (M⁺ --CONEtCO--).

Anal. Calcd.: C, 54.92; H, 3.51; N, 6.10; Found: C, 54.92; H, 3.40; N,6.13.

M.P. 153°-154° C.

The following compound was obtained in substantially the same manner asthat of Example 1, Steps e, f):

2-[(4-Bromo-2-fluorophenyl)methyl]-1'-ethyl-6-fluorospiro[isoquinoline-4(H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

¹ H NMR (DMSO-d₆, 400 MHz): δ1.0 (t, J=7.17 Hz, 3H, --NCH₂ CH₃),3.41-3.48 (m, 4H, --CH₂ CONEt--, --NCH₂ CH₃), 5.05 (s, 2H, --NCH₂ --),7.14 (t, J=8.2 Hz, 1H, Ar-H), 7.33 (dd, J=8.2 Hz, 1.66 Hz, 1H, Ar-H),7.47 (dt, J=8.6 Hz, 2.47 Hz, 1H, Ar-H), 7.52 (dd, J=9.8 Hz, 1.9 Hz, 1H,Ar-H), 7.72 (dd, J=9.8 Hz, 1H, 2.42 Hz, 1H, Ar-H), 8.23 (dd, J=8.8 Hz,5.86 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1720 (s), 1695 (s).

M/S (m/e): 476 (M⁺), 405 (M⁺ --CONEt--), 377 (M⁺ --CONEtCO--).

Anal. Calcd.: C, 52.85; H, 3.17; N, 5.87; Found: C, 52.71; H, 2.97; N,5.84.

M.P. 185°-186° C.

2-[(4-Bromo-2-fluorophenyl)methyl]-1'-methylspiro[isoquinoline-4(H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

A mixture of2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticacid (2.0 g, 4.31 mmol) and SOCl₂ (10 g) was refluxed for 1 hour. Thevolatiles were removed in vacuo and the acid chloride was dissolved inTHF (10 mL). In a second flask was placed a freshly prepared saturatedNH₂ Me/THF solution (20 mL) and the contents of the first flask wereadded slowly. After 10 minutes the mixture was poured into H₂ O,acidified with HCl (2N), extracted with EtOAc and the organic extractswere dried over MgSO₄. Evaporation and purification by flashchromatography (hexane/EtOAc, 4/1) gave an off-white solid which wasrecrystallized from ether/hexane (at -20° C.) to give a white solid (1.2g, 62.5%).

¹ NMR (DMSO-d₆, 400 MHz): δ2.93 (s, 3H, CH₃), 3.32 (s, 3H, --CO₂ CH₃),3.41 (d, J=18.2 Hz, 1H, --CH₂ CONMe--), 3.54 (d, J=18.2 Hz, 1H, --CH₂CONMe--), 5.07 (s, 2H, --NCH₂ --), 7.16 (t, J=8.3 Hz, 1H, Ar-H), 7.33(dd, J=8.3 Hz, 2.5 Hz, 1H, Ar-H), 7.54 (dd, J=9.96 Hz, 2.07 Hz, 1H,Ar-H), 7.61-7.67 (m, 2H, Ar-H), 7.77 (dt, J=7.26 Hz, 1.45 Hz, 1H, Ar-H),8.16 (dd, J=8.3 Hz, 1.87 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1710 (s), 1680 (s).

MS (m/e): 444 (M⁺), 387 (M⁺ --CONMe--), 359 (M⁺ --CONMeCO--).

Anal. Calcd.: C, 53.95; H, 3.17; N, 6.29; Found: C, 53.69; H, 2.87; N,6.21.

M.P. 78°-79° C.

EXAMPLE 22-[[5-(Trifluoromethyl)-2-benzothiazolyl]methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone Step G)3-Methoxy-1-oxo-1H-2-benzopyran-4-carboxylic Acid Methyl Ester

A mixture of (2-carboxyphenyl)propanedioic acid dimethyl ester (10.09 g,39.68 mmol) and SOCl₂ (100 g) was refluxed for 2 hours. The volatileswere removed in vacuo and the crude product (acid chloride) wasdissolved in THF (200 mL). Triethylamine (27.64 mL, 198.4 mmol) wasadded and the mixture was stirred for 30 minutes. The yellowishsuspension was poured into HCl (1N, 1000 mL), extracted with EtOAc andthe organic extracts were dried over MgSO₄. Evaporation andcrystallization from acetone/ether/hexane (at -20° C.) gave a whitesolid (87.6 g, 94.4%).

¹ H NMR (DMSO-d₆, 400 MHz): δ3.82 (s, 3H, --CO₂ Me), 4.03 (s, 3H,--OMe), 7.42 (t, J=7.26 Hz, 1H, Ar-H), 7.8 (t, J=8.2 Hz, 1H, Ar-H), 7.9(d, J=8.3 Hz, 1H, Ar-H), 8.1 (d, J=7.26 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1740 (C=O), 1685 (C=O).

MS (m/e): 234 (16, M⁺), 206 (38.5, M⁺ --CO), 203 (12, M⁺ --OMe).

Anal. Calcd.: C, 61.59; H, 4.30; Found: C, 61.82; H, 4.29.

M.P. 129°-130° C.

The following compound was prepared in substantially the same manner asthat of Example 1, Step g):

6-Fluoro-3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic Acid Methyl Ester

¹ H NMR (DMSO-d₆, 400 MHz): δ3.81 (s, 3H, --CO₂ CH₃), 4.06 (s, 3H,--OCH₃), 7.27 (dt, J=8.3 Hz, 1H, Ar-H), 7.8 (dd, J=11.83 Hz, 2.49 Hz,1H, Ar-H), 8.16 (dd, J=8.92 Hz, 6.2 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1750 (C=O), 1685 (C=O).

MS (m/e): 252 (24, M⁺), 224 (54, M⁺ --CO).

Anal. Calcd.: C, 57.15; H, 3.60; Found: C, 57.19; H, 3.57.

M.P. 142°-143° C.

Step H) 2-(Cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

To a solution of 3-methoxy-1-oxo-1H-2-benzopyran-4-carboxylic acidmethyl ester (8.0 g, 34.19 mmol) in DMF (100 mL) was addedaminoacetonitrile hydrochloride (6.32 g, 68.37 mmol) and the suspensionwas stirred until all the materials have dissolved. Triethylamine (14.3mL, 102.57 mmol) was added and the mixture was stirred at 100° C. for 30minutes, and then poured into H₂ O, acidified with HCl (2N) andextracted with EtOAc. The organic extracts were dried over MgSO₄.Evaporation and crystallization from acetone/ether/hexane (at -20° C.)gave a yellowish solid (6.5 g, 73.7%).

¹ H NMR (DMSO-d₆, 400 MHz): δ[3.7 (s), 3.98 (s), 3H, --CO₂ CH₃,rotameric], [4.92 (s), 5.44 (s), 2H, --NCH₂ CN, rotameric], 7.2-8.4 (m,4H, Ar-H, rotameric).

IR (KBr, cm⁻¹): 3400 (OH), 1670 (C=O).

MS (m/e): 258 (20, M⁺), 226 (43, M⁺ --MeOH), 199 (13, M⁺ --CO₂ Me).

Anal. Calcd.: C, 60.47; H, 3.90; N, 10.85; Found: C, 60.27; H, 3.77; N,10.69.

M.P. 169°-171° C.

The following compound was prepared in substantially the same manner asthat of Example 1, Step h):

2-(Cyanomethyl)-6-fluoro-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinolinecarboxylic Acid Methyl Ester

Anal. Calcd.: C, 56.53; H, 3.28; N, 10.14; Found: C, 56.45; H, 3.22; N,10.13.

M.P. 178°-179° C.

Step I)

2-(Cyanomethyl)-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid 1,1-Dimethylethyl Ester

To a suspension of2-(cyanomethyl)-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylicacid methyl ester (6.5 g, 25.19 mmol), K₂ CO₃ (6.95 g, 50.38 mmol) andanhydrous DMF (100 mL) was added tert-butyl bromoacetate (6.1 mL, 37.79mmol). After stirring at 85° C. for 3 hours, the mixture was poured intoH₂ O, acidified with HCl (2N) and extracted with EtOAc. The organicextracts were dried over MgSO₄. Evaporation and purification by flashchromatography on silica gel (hexane/EtOAc 4/1) gave a white solid (8.5g, 90.7%).

¹ H NMR (DMSO-d₆, 200 MHz): δ1.03 (s, 9H, --CO₂ CMe₃), 3.58 (s, 3H,--CO₂ CH₃), 3.64 (s, 2H, --CH₂ CO₂ --), 5.05 (s, 2H, --NCH₂ CN), 7.64(m, 2H, Ar-H). 7.78 (dd, J=7.4 Hz, 2.0 Hz, 1H, Ar-H), 8.24 (dd, J=8.2Hz, 1.6 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 1745 (C=O), 1730 (C=O), 1670 (C=O).

MS (m/e): 373 (38, M⁺ +H), 317 (100, M⁺ +H, --CME₃)

Anal. Calcd.: C, 61.28; H, 5.41; N, 7.52; Found: C, 61.61; H, 5.49; N,7.13.

M.P. 48°-50° C.

The following compound was obtained in substantially the same manner asthat of Example 1, Step i):

2-(Cyanomethyl)-6-fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticAcid 1,1-Dimethylethyl Ester

Anal. Calcd.: C, 58.46; H, 4.91; N, 7.18; Found: C, 58.65; H, 4.98; N,7.08.

M.P. 133°-135° C.

Step J)1,2,3,4-Tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-2-[[(5-trifluoromethyl)-2-benzothiazolyl]methyl]-4-isoquinolineaceticAcid

To a mixture of 3-amino-4-mercaptobenzotrifluoride hydrochloride (6.1 g,26.2 mmol) and EtOH (150 mL) was added Et₃ N (3.65 mL). After stirringfor 10 minutes,2-(cyanomethyl)-1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-4-isoquinolineaceticacid 1,1-dimethylethyl ester (6.5 g, 17.47 mmol) was added and themixture was refluxed for 15 hours, poured into H₂ O, acidified with HCl(2N) and extracted with EtOAc. The organic extracts were dried overMgSO₄. Evaporation gave an oil (9.6 g) which was dissolved in CH₂ Cl₂(80 mL). Trifluoroacetic acid (20 mL) was added and the mixture wasstirred at room temperature for 8 hours. The volatiles were removed invacuo and the residue was purified by flash chromatography on acidwashed (5%, H₃ PO₄ in MeOH) silica gel to give a white solid (6.3 g,73.3%).

¹ H NMR (DMSO-d₆, 400 MHz): δ3.57 (s, 3H, --CO₂ CH₃), 3.68 (dd, J=17.85Hz, 2H, --CH₂ CO₂ H), 5.61 (s, 2H, --NCH₂ --), 7.62 (m, 2H, Ar-H), 7.81(m, 2H, Ar-H), 8.2 (dd, J=7.9 Hz, 1.04 Hz, 1H, Ar-H), 8.33 (dd, J=8.5Hz, 0.92 Hz, 1H, Ar-H), 8.34 (d, J=0.83 Hz, 1H, Ar-H).

IR (KBr, cm⁻¹): 3200-2500 (CO₂ H), 1750 (C=O), 1710 (C=O), 1670 (C=O).

MS (m/e): 492 (6, M⁺), 448 (6, M⁺ --CO₂), 416 (62, M⁺ --CO₂, --MeOH).

Anal. Calcd.: C, 53.66; H, 3.07; N, 5.69; Found: C, 53.40; H, 3.01; N,5.54.

M.P. 199°-201° C.

The following compounds were prepared in substantially the same manneras that of Example 1, Step j):

1,2,3,4-Tetrahydro-4-(methoxycarbonyl-1,3-dioxo-2-[(2-benzothiazolyl)methyl]-4-isoquinolineaceticAcid

Anal. Calcd.: C, 59.43; H, 3.80; N, 6.60; Found: C, 59.37; H, 3.74; N,6.43.

M.P. 189°-190° C.

6-Fluoro-1,2,3,4-tetrahydro-4-(methoxycarbonyl-1,3-dioxo-2-[[(5-trifluoromethyl)-2-benzothiazolyl]methyl]-4-isoquinolineaceticAcid

Anal. Calcd.: C, 51.77; H, 2.76; N, 5.49; Found: C, 51.62; H, 2.97; N,5.18.

M.P. 103°-105° C.

Step K)2-[(5-Trifluoromethyl)-2-benzothiazolyl]methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

A mixture of1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-2-[[(5-trifluoromethyl)-2-benzothiazolyl)methyl]-4-isoquinolineaceticacid (2.0 g, 4.06 mmol) and SOCl₂ (20 g) was refluxed for 1 hour. Thevolatiles were removed in vacuo and the product (acid chloride) wasdissolved in THF (10 mL). To a second flask was placed a freshlyprepared, saturated NH₂ Me/THF solution (20 mL) and the contents of thefirst flask were added slowly. After stirring for 10 minutes, themixture was poured into H₂ O (500 mL) acidified with HCl (2N) extractedwith EtOAc and dried over MgSO₄. Evaporation and purification by flashchromatography (hexane/EtOAc 2/1) gave a white solid (1.35 g, 80.3%).

¹ H NMR (DMSO-d₆, 400 MHz): δ2.96 (s, 3H, N--CH₃), 3.43 (d, J=18.26 Hz,1H, --HCHCO--), 3.56 (d, J=18.26 Hz, 1H, --HCHCO--), 5.56 (s, 2H, --NCH₂--), 7.66 (m, 2H, Ar-H), 7.82 (m, 2H, Ar-H), 8.20 (d, J=7.88 Hz, 1H,Ar-H), 8.33 (m, 2H, Ar-H).

IR (KBr, cm⁻¹): 1720 (C=O), 1700 (C=O), 1670 (C=O).

MS (m/e): 473 (100, M⁺).

Anal. Calcd.: C, 55.81; H, 2.98; N, 8.88; Found: C, 56.22; H, 2.97; N,8.80.

M.P. 179°-180° C.

The following compound was prepared in substantially the same manner asthat of Example 1, Step k):

1'-Ethyl-6-fluoro-2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone

Anal. Calcd.: C, 54.66; H, 2.99; N, 8.31; Found: C, 54.97; H, 2.88; N,8.35.

M.P. 154°-156° C.

We claim:
 1. The compounds of structural formula (I) ##STR9## wherein R¹and R² are independently hydrogen, alkyl containing 1 to 6 carbon atoms,halogen, lower alkoxy containing 1 to 6 carbon atoms, trifluoromethyl,nitro, aryl or aryl(lower alkyl)oxy wherein aryl contains 6 to 10 carbonatoms and lower alkyl contains 1 to 6 carbon atoms; R³ is hydrogen,lower alkyl containing 1 to 6 carbon atoms, aryl, aryl(lower alkyl) orhalogen substituted aryl(lower alkyl) wherein aryl contains 6 to 10carbon atoms and lower alkyl contains 1 to 6 carbon atoms, orbenzothiazole of structural formula ##STR10## wherein R⁵ is hydrogen,alkyl containing 1 to 6 carbon atoms, lower alkoxy containing 1 to 6carbon atoms, trifluoromethyl, nitro, aryl or aryl(lower alkyl)oxywherein aryl contains 6 to 10 carbon atoms and lower alkyl contains 1 to5 carbon atoms; and R⁴ is alkyl containing 1 to 12 carbon atoms, aryl,aryl(lower alkyl) wherein aryl contains 6 to 10 carbon atoms and loweralkyl contains 1 to 6 carbon atoms, acyl, carboalkoxy, or --(CH₂)_(n)CO₂ H, --(CH₂)_(n) OH, wherein n is 1 to
 6. 2. The compounds accordingto claim 1 wherein R¹ and R² are independently hydrogen or halogen; R³is a mono- or dihalogen substituted aryl(lower alkyl) wherein arylcontains 6 carbon atoms and lower alkyl contains 1 to 3 carbon atoms, orbenzothiazole of structural formula ##STR11## wherein R⁵ is hydrogen,halogen or trifluoromethyl; and R⁴ is alkyl containing 1 to 3 carbonatoms.
 3. The compound according to claim22-[(4-bromo-2-fluorophenyl)methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.
 4. The compound according toclaim22-[(4-bromo-2-fluorophenyl)methyl]-1'-ethylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.
 5. The compound according toclaim22-[(4-bromo-2-fluorophenyl)methyl]-1'-ethyl-6-fluorospiro[isoquinoline-4(1H,3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.6. The compound according to claim22-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1'-methylspiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.
 7. The compound according toclaim21'-ethyl-6-fluoro-2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone.
 8. A pharmaceutical compositionfor preventing or relieving neuropathy, nephropathy, retinopathy, orcataracts in a diabetic mammal, which comprises an effective amount ofclaim 1 and a pharmaceutically acceptable carrier.
 9. A method ofpreventing or relieving neuropathy, nephropathy, retinopathy, orcataracts in a diabetic mammal, which comprises administering to saidmammal an alleviating or prophylatic amount of a compound of claim 1.